Parkin protects against mitochondrial toxins and beta -amyloid accumulation in skeletal muscle cells

doi:10.1074/jbc.M512649200

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Papers In Press, published online ahead of print March 3, 2006
J. Biol. Chem, 10.1074/jbc.M512649200
Submitted on November 28, 2005
Revised on February 22, 2006
Accepted on March 3, 2006

Parkin protects against mitochondrial toxins and $beta$ -amyloid accumulation in skeletal muscle cells

Kenneth M. Rosen, Vimal Veereshwarayya, Charbel E-H Moussa, Qinghao Fu, Matthew S. Goldberg, Michael G. Schlossmacher, Jie Shen, and Henry W. Querfurth

Neurology Dept., Caritas St. Elizabeth's Medical Center, Boston, MA 02135

Corresponding Author: kenneth_rosen{at}cchcs.org

Mutations in the ubiquitin ligase-encoding Parkin gene have been implicated in the pathogenesis of autosomal recessive Parkinson disease. Outside of the central nervous system, Parkin is prominently expressed in skeletal muscle. We have found accumulations of Parkin protein in skeletal muscle biopsies taken from patients with Inclusion Body Myositis (IBM), a degenerative disorder in which intramyofiber accumulations of the $beta$ -amyloid peptide are pathognomonic. In comparing primary cultures of skeletal muscle derived from parkin knockout and wild-type mice, we have found the absence of parkin to result in greater sensitivity to mitochondrial stressors rotenone and carbonyl cyanide 3-chlorophenylhydrazone, without any alteration in sensitivity to calcium ionophore or hydrogen peroxide. Utilizing viral expression constructs coding for the Alzheimer’s disease and IBM-linked $beta$ -amyloid precursor protein ( $beta$ APP) and for its metabolic byproducts A $beta$ 42 and C100, we find that parkin knockout muscle cells are also more sensitive to the toxic effects of intracellular A $beta$ . We also constructed a lentiviral system to overexpress wild-type Parkin, and show that boosting the levels of parkin expression in normal skeletal muscle cultures provides substantial protection against both mitochondrial toxins and overexpressed $beta$ -amyloid. Correspondingly, exogenous Parkin significantly lowered A $beta$ levels. These data support the hypothesis that in myocytes parkin has dual properties in the maintenance of skeletal muscle mitochondrial homeostasis and in the regulation of A $beta$ levels.

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Parkin protects against mitochondrial toxins and -amyloid accumulation in skeletal muscle cells

Parkin protects against mitochondrial toxins and $beta$ -amyloid accumulation in skeletal muscle cells